Functional Dosage of Muscarinic Cholinergic Receptor 3 Signalling, Not the Gene Dose, Determines Its Hypertension...

Area of Science:

• Genetics
• Physiology
• Pharmacology

Background:

• Quantitative trait loci (QTLs) for blood pressure (BP) are numerous but poorly understood, especially in humans.
• The causal gene for C17QTL1 in Dahl salt-sensitive rats, Chrm3 (encoding M3R), was investigated for its role in hypertension.
• Functional identification and pathogenic directionality of BP-related QTLs remain challenging.

Purpose of the Study:

• To investigate the role of Chrm3 and its encoded M3R in the pathogenesis of polygenic hypertension.
• To determine the functional impact of specific Chrm3 mutations on BP regulation.
• To explore M3R-mediated signaling as a potential therapeutic target for hypertension.

Main Methods:

• Utilized congenic knock-ins and gene-specific knockout in Dahl salt-sensitive rats.
• Performed ex vivo and in vivo functional studies to assess M3R activity and BP.
• Analyzed the effects of a Chrm3 missense mutation and M3R domain deletions on BP and signaling.

Main Results:

• A Chrm3 missense mutation (T1667C) increased BP by enhancing M3R signaling, resensitization, and adrenal epinephrogenesis.
• Abolishing M3R function via gene targeting decreased BP, confirming M3R's hypertensive role.
• Deletion of 8 amino acids in the M3R extracellular loop did not affect BP.

Conclusions:

• M3R-mediated signaling represents a novel pathway in hypertension pathogenesis, linked to epinephrine secretion.
• Specific M3R missense mutations influencing BP can be identified as potential diagnostic targets.
• Understanding M3R structure-function relationships provides insights into hypertension mechanisms.